Human 8-oxoguanine-DNA glycosylase (OGG1) is the major enzyme for repairing 8-oxoguanine (8-oxoG), a highly mutagenic guanine base lesion produced by reactive oxygen species. A role for OGG1 in the prevention of cancer is suggested by the frequent absence of the OGG1 allele in human lung tumors and the increased incidence of lung tumors in mice lacking a functional OGG1. Additionally, polymorphic variants of OGG1 are prevalent in human populations and are positively correlated with cancer incidence. A frequently occurring OGG1 polymorphism results in the substitution of serine 326 for cytosine (S326C). The 326 C/C genotype is strongly linked to numerous cancers, including lung, prostate, colon, and orolaryngeal cancers, with 326 C/C individuals being up to 7-fold more likely to develop cancers compared to individuals of the normal 326 S/S genotype. The S326C OGG1 protein has enzymatic activity comparable to the wild-type protein, thus the mechanism of associated cancer susceptibility is unclear. Our analysis of the OGG1 amino acid sequence revealed a PEST-like calpain cleavage site that encompasses the polymorphism site. Using purified recombinant proteins, we showed OGG1 to be a substrate of the calcium-dependent protease calpain. Sequencing of OGG1 protein cleaved by calpain showed that calpain removes the C-terminal OGG1 nuclear localization signal (NLS). We tested the possibility that the S326C polymorphism might affect OGG1 cleavage by calpain. The S326C OGG1 variant was found to be resistant to calpain cleavage. Our in vivo studies in human cells have shown that the wild-type OGG1 loses the NLS and is translocated to the cytoplasm upon treatment with ionomycin, a calcium ionophore that activates cellular calpain. The activation of calpain following a calcium influx in response to oxidative stress and DNA damage is an obligatory step in the caspase-dependent apoptotic pathway. We hypothesize that the differential cleavage of the mutant OGG1 by calpain may abort an important step in DNA damage-induced cell death. High-level calpain activation in response to DNA damage serves as an apoptosis signal that may be partially ignored with respect to 8-oxoG repair in cells harboring S326C OGG1. We propose that cells having sustained overwhelming DNA damage that should become apoptotic may continue to attempt to repair DNA in S326C cells, thereby allowing the survival of cells with genomic instability that leads to carcinogenesis.